Certain substituted amides having a physiological cooling effect

ABSTRACT

Cyclic and acyclic amides, substituted ureas and sulphonamides are disclosed having the property of stimulating the cold receptors of the nervous system of the body to produce a cold sensation and are used for this purpose in a variety of edible and topical preparations.

This is a division of application Ser. No. 568,663 filed Apr. 16, 1975,now U.S. Pat. No. 4,044,120.

FIELD OF INVENTION

This invention relates to compositions and compounds having aphysiological cooling effect on the skin and on the mucous membranes ofthe body, particularly those of the mouth, nose, throat andgastrointestinal tract.

BACKGROUND OF THE INVENTION AND PRIOR ART

Menthol is well known for its physiological cooling effect on the skinand mucous membranes of the mouth and has been extensively used as aflavouring agent (menthol being a major constituent of oil ofpeppermint) in foodstuffs, beverages, dentifrices, mouthwashes etc. andas a component in a wide range of toiletries, liniments and lotions fortopical application. Menthol is also a well known tobacco additive forproducing a `cool` sensation in the mouth when smoking.

It is well established that the `cooling` effect of menthol is aphysiological effect due to the direct action of menthol on the nerveendings of the human body responsible for the detection of hot or coldand is not due to latent heat of evaporation. It is believed that thementhol acts as a direct stimulus on the cold receptors at the nerveendings which in turn stimulate the central nervous system.

Although menthol is well established as a physiological coolant its use,in some compositions, is circumscribed by its strong minty odour and itsrelative volatility.

A few other compounds have been reported in the technical literature ashaving an odour or flavour similar to menthol and from time to time havebeen proposed as flavourants or odourants in a variety of topical andingestible compositions. For example, Japanese Patent Publication No.39-19627 reports that 3-hydroxymethyl p-menthane (menthyl carbinol) hasa flavour closely resembling that of 1-menthol and suggests its use as aflavourant in confectionery, chewing gum, and tobacco. In Swiss PatentNo. 484,032 certain saccharide esters of menthol are proposed asadditives to tobacco. In French Patent Specification No. 1,572,332N,N-dimethyl 2-ethylbutanamide is reported as having a minty odour andrefreshing effect, and the minty odour of N,N-diethyl2,2-dimethylpropanamide is also referred to. A similar effect isreported for N,N-diethyl 2-ethylbutanamide in Berichte 39, 1223, (1906).A minty odour has also been reported for 2,4,6-trimethylheptan-4-ol and2,4,6-trimethyl hept-2-en-4-ol in Parfums-Cosmetiques-Savons, May 1956,pp. 17-20. The cooling effect of menthol and other related terpenealcohols and their derivatives has also been studied and reported inKoryo, 95, (1970) pp. 39-43. 2,3-p-menthane diol has also been reportedas having a sharp cooling taste (Beilstein, Handbuch der OrganischenChemie, 4th Ed. (1923) vol. 6, p.744). Still other substitutedp-menthanes having a physiological cooling effect are disclosed inGerman Offenlegungsschrift Nos. P 22 02 535, P 22 03 947, P 22 03 273and P 22 05 255.

Despite this knowledge of other compounds having an odour and flavoursimilar to that of menthol, menthol is still extensively used intopical, ingestible and other compositions notwithstanding thedisadvantages mentioned above, namely its very strong odour and itsrelative volatility, and despite its high cost.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide other compoundshaving a pronounced physiological cooling effect, in many cases morepersistent than that obtained with menthol, without the attendantdisadvantages of a strong minty odour.

It is a further object to provide compounds having a pronouncedphysiological cooling effect and being of relatively low volatility.

It is a further object of the present invention to provide ingestible,topical and other compositions capable of stimulating the cold receptorsof the nervous system of the human body thereby to create a desirable`cool` sensation, and a method of making them.

It is a yet further object of the present invention to provide a methodof stimulating the cold receptors of the nervous system of the body tocreate a cool sensation.

A further object is to provide compounds having physiological activitywhich are inexpensive and easily synthesised from readily availablestarting materials.

Other objects will be apparent from the following detailed descriptionof the invention.

SUMMARY OF INVENTION

The present invention is based on the discovery of a group of cyclic andacyclic amides, substituted ureas and sulphonamides which have apronounced physiological cooling activity, but which are without thestrong minty smell of menthol, and which are inexpensive and easilysynthesised from readily available starting materials.

The compounds discovered in accordance with this invention may berepresented by the formula: ##STR1## where R₁, when taken separately, isH, C₁ -C₇ alkyl or C₃ -C₆ cycloalkyl;

R₂, when taken separately, is C₃ -C₈ alkyl or C₃ -C₈ alkylcycloalkyl,alkylcycloalkylalkyl, cycloalkyl, or cycloalkylalkyl, with the provisothat R₂ is branched at an alpha carbon atom relative to the N atom whenR₁ is H or at an alpha or beta carbon atom when R₁ is alkyl orcycloalkyl, this condition to be satisfied, in the case of cyclicgroups, when the carbon atom alpha or beta to the N atom is part of thecycle;

R₁ and R₂, when taken together, represent a straight or branched chainalkylene group forming with the N atom to which they are attached a 5-10membered heterocycle, and preferably having branching at an alpha orbeta carbon atom relative to the N atom;

R₁ and R₂ when separate groups and when taken together provide a totalof at least 5 carbon atoms; and

X represents R₃ CO--, R₄ SO₂ -- or R₅ R₆ NCO--, where:

R₃ is H, C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₂ -C₈ hydroxyalkyl, C₂ -C₈carboxyalkyl or C₃ -C₈ alkylcarboxyalkyl, with the proviso that when R₃is C₆ alkyl it is primary in structure;

R₄ is C₁ -C₆ alkyl or C₃ -C₆ cycloalkyl, with the proviso that when R₄is C₅ or C₆ alkyl it is primary in structure;

R₅ and R₆, when taken separately, are each H, C₁ -C₆ alkyl, C₃ -C₆alkylcycloalkyl, cycloalkyl, or cycloalkylalkyl, C₂ -C₈ hydroxyalkyl, C₂-C₈ carboxyalkyl or C₃ -C₈ alkylcarboxyalkyl; or together represent astraight or branched chain C₃ -C₁₀ alkylene group optionally containingan ether oxygen atom; and where:

R₁, R₂ and X provide a total of from 7-16 carbon atoms.

STATEMENT OF INVENTION

In accordance with this invention, therefore, there are providedconsumer products for application to or consumption by the human bodyinto which there is incorporated a means for stimulating the coldreceptors of the nervous system of the human body wherein said meanscomprise an effective amount of one or more compounds of the formulahereinbefore set forth.

By consumer products we means a manufactured product applied to orconsumed by the human person for toilet, cosmetic, hygienic, nutritive,curative, prophylactic, or other purposes and constituting a vehicle bymeans of which the said compounds may be brought into contact with theskin, mucous membranes or other surface tissues of the body, whetherexternal tissues or internal, for example, of the nose, throat, mouthand gastrointestinal tract, and includes liquid and solid phasepreparations of an essentially formless nature e.g. solutions,emulsions, pastes, ointments, powders etc., solid phase preparations ofsemi-permanent form, e.g. shaped toilet and cosmetic preparations andshaped edible preparations, whose shaped form is only temporary andwhich lose that form on use, and articles of permanent form but whichare of an essentially disposable nature, e.g. cleansing tissues,toothpicks, etc.

Typical consumer products into which the compounds of this invention maybe incorporated and which may therefore serve as vehicles forapplication of the compounds to the person are:

1. Edible and potable compositions including alcoholic and non-alcoholicbeverages; confectionery, chewing gum, cachous; ice cream; jellies;

2. Toiletries including after-shave lotions, shaving soaps, creams andfoams, toilet water, deodorants and antiperspirants, "solid colognes",toilet soaps, bath oils and salts, shampoos, hair oils, talcum powders,face creams, hand creams, sunburn lotions, cleansing tissues,dentifrices, toothpicks, mouthwashes, hair tonics, eyedrops;

3. Medicaments including antiseptic ointments, pile ointments,liniments, lotions, decongestants, counter-irritants, cough mixtures,throat lozenges, antacid and indigestion preparations, and analgesics;

4. Miscellaneous compositions such as water soluble adhesivecompositions for envelopes, postage stamps, adhesive labels etc.

5. Tobacco and tobacco-containing preparations, e.g. cigarettes, pipetobacco, chewing tobacco, snuff, cigars etc.

DETAILED DESCRIPTION

The compounds of formula I useful as cold receptor stimulants inaccordance with this invention fall into three classes: cyclic andacyclic amides, i.e. compounds of formula I, where X is R₃ CO--,;substituted ureas, i.e. compounds of formula I where X is R₅ R₆ NCO--;and sulphonamides, i.e. compounds of formula I where X is R₄ SO₂ --. Ofthe three classes, the substituted ureas and the cyclic and acyclicamides are much to be preferred over the sulphonamides by reason ofgenerally higher levels of physiological cooling activity, greaterstability and cheaper manufacture. By reason of high levels of activityand cheapness, the substituted ureas are generally to be preferred overthe cyclic and acyclic amides. The three classes of active compound willbe discussed separately.

Substituted Ureas

Broadly speaking the compounds of highest activity are the substitutedureas which may be represented by the formula II: ##STR2## where R₁, R₂,R₅ and R₆ are as defined above. Preferred substituted ureas are thosecompounds where R₁ is H or C₁ -C₇ alkyl, R₂ is C₃ -C₈ alkyl or C₃ -C₈cycloalkyl, cycloalkylalkyl or alkylcycloalkyl, R₂ having branching inan alpha position relative to the N atom when R₁ is H, or at an alpha orbeta position when R₁ is alkyl, or where R₁ and R₂ are joined to form analkylene group having up to 10 carbon atoms and having branching at analpha or beta position relative to the N atom, and forming together withthe nitrogen atom a 5- to 7-membered ring; and where R₅ is H or C₁ -C₆alkyl and R₆ is C₁ -C₆ alkyl, or C₃ -C₆ cycloalkyl, or where R₅ and R₆jointly represent an alkylene group, optionally containing an etheroxygen atom and forming with the N atom a 5- or 6-membered ring.

The substituted ureas of formula II may be easily prepared by reactionof an appropriate amine with an isocyanate or carbamoyl chloride, thefollowing being a typical reaction scheme: ##STR3##

Cyclic and Acyclic Amides

The cyclic and acyclic amides useful in this invention may berepresented by formula III: ##STR4## where R₁, R₂ and R₃ are as definedabove in connection with formula I. Preferred values for R₁ and R₂ areas set out above for formula II and the preferred values for R₃ are H,C₁ -C₆ alkyl, C₂ -C₆ hydroxyalkyl, carboxyalkyl or alkylcarboxyalkyl andC₃ -C₆ cycloalkyl.

The amides may readily be prepared by reaction of the appropriate acidchloride and a substituted amine in accordance with procedures wellknown for the preparation of amides e.g.

    R.sub.1 R.sub.2 NH + R.sub.3 COCl → R.sub.1 R.sub.2 NCOR.sub.3

Cyclic and Acyclic Sulphonamides

Although less preferred than the substituted ureas and amideshereinbefore described, but nevertheless still possessing utility in thecompositions of this invention, are sulphonamides of formula IV:##STR5## where R₁, R₂ and R₄ are as above defined in connection withformula I. Preferred values of R₁ and R₂ are as defined above inconnection with formula II, whilst the preferred values for R₄ are C₁-C₄ alkyl.

The sulphonamides of formula IV may readily be prepared from thecorresponding sulfonyl chloride and substituted amine by procedures wellknown in the art e.g.

    R.sub.1 R.sub.2 NH + R.sub.5 SO.sub.2 Cl → R.sub.1 R.sub.2 NSO.sub.2 R.sub.5

As will be apparent from the above formulae some of the compounds usedas cold receptor stimulants in accordance with this invention exhibiteither geometric or optical isomerism or both and, depending on thestarting materials and the methods used in their preparation thecompounds may be isomerically pure, i.e. consisting of one geometric oroptical isomer, or they may be isomeric mixtures, both in the geometricand optical sense. Generally, the compounds will be used as isomericmixtures, but in some cases the cooling effect may differ as betweengeometric or optical isomers, and therefore one or other isomer may bepreferred.

For the purposes of the present disclosure the following test procedurehas been devised as a means to identify compounds having a physiologicalcooling activity in accordance with the present invention and hereinreferred to as cold receptor stimulants. This test is intended purely asa means for identifying compounds having a physiological coolingactivity and useful in the present invention and for giving anindication of the different relative activities of the compounds, asbetween themselves and as compared with menthol, when applied in aparticular manner to a particular part of the body. The results are notnecessarily indicative of the activity of these compounds in otherformulations and other parts of the body where other factors come intoplay. For example, a controlling factor in the onset of cooling effect,its intensity and longevity will be the rate of penetration of thecompounds through the epidermis and this will vary in differentlocations on the human body. The formulation of actual productsaccording to this invention will therefore be done largely on anempirical basis although the test results and other figures given hereinwill be useful as a guide, particularly in the formulation of productsfor oral administration, since the test procedure to be describedinvolves oral application of the compound. A similar test may, ofcourse, be devised for the purposes of measuring the relative activitiesof the compounds on another area of the body, for example, the face orforearm, and this will be a useful guide in the choice of compounds tobe used in preparations for external topical usage.

It will also be noted that the described test procedure is done on astatistical basis. This is necessary since sensitivity to thesecompounds will vary not only from compound to compound and from one partof the body to another, but also from one individual to another. Testsof this nature are commonly used in the testing of the organolepticproperties, e.g. taste, smell etc. of organic and inorganic compounds,see Kirk-Othmer: Encyclopedia of Chemical Technology, 2nd Ed. (1967)Vol. 14, pages 336-344.

Test Procedure

The following test procedure is aimed at determining the minimumquantity of the test compound required to produce a noticeable coolingeffect in a person of average sensitivity, this minimum quantity beingtermed the threshold for that particular compound. The tests are carriedout on a selected panel of 6 people of median sensitivity to 1-menthol.

Panel Selection

To select a test panel of average sensitivity the following procedure isused. Known quantities of 1-menthol in solution in petroleum ether (bp.40-60) are placed on 5 mm. squares of filter paper, whereafter thesolvent is allowed to evaporate. A panel of observers is enrolled andasked to place one impregnated square at a time on the tongue and toreport on the presence or absence of a cooling effect. The quantity of1-menthol on each impregnated square is gradually reduced from a valuesubstantially above 0.25 μg. per square to substantially below 0.25 μg,the precise range being immaterial. Conveniently, one starts withsquares containing 2.0 μg 1-menthol, the amount on each successivesquare being half that of the preceding square, i.e. the second testsquare will contain 1.0 μg, the third 0.5 μg, and so on. Each quantityis tested on the tongue at least 10 times. In this way, the thresholdsto cold receptor stimulus by 1-menthol are determined for eachindividual of the panel, the threshold for each individual being thatamount of 1-menthol for which, in a series of not less than 10 testapplications, a cooling effect is reported 50% of the time. Six panelmembers are now selected whose threshold is approximately 0.25 μg, thisselect panel being regarded as the test panel of average sensitivity.

Compound Testing

To test the activity of compounds according to this invention, the aboveprocedure is repeated using only the 6 selected panel members of averagesensitivity to 1-menthol. The individual thresholds for each testcompound on each of the 6 selected panel members are determined andaveraged. Those compounds whose average threshold on the select testpanel is 100 μg or less are regarded as having cooling activity inaccordance with this invention.

Test Results

The following tables set out the relative cooling activities ofcompounds of the formula defined above when tested according to theforegoing procedure.

                                      Table I                                     __________________________________________________________________________     ##STR6##                                                                                                                       Activity                    Compound                                          bp. or                       R.sub.1      R.sub.2      R.sub.5    R.sub.6     mp. (° C)                                                                    μg                 __________________________________________________________________________    sec-C.sub.4 H.sub.9                                                                        sec.C.sub.4 H.sub.9                                                                        H          C.sub.2 H.sub.5                                                                            98-102° /                                                                    1                                                                       0.2 mm                      seo-C.sub.4 H.sub.9                                                                        seo-C.sub.4 H.sub.9                                                                        H          CH.sub.3     87-90°                                                                       1.5                                                                     (m.p.)                      n-C.sub.4 H.sub.9                                                                          t-C.sub.4 H.sub.9                                                                          H          C.sub.2 H.sub.5                                                                            90-92° /                                                                     1                                                                       0.2 mm.                     iso-C.sub.3 H.sub.7                                                                        iso-C.sub.3 H.sub.7                                                                        C.sub.2 H.sub.5                                                                          H            88-92° /                                                                     5                                                                       0.8 mm                      n-C.sub.5 H.sub.11                                                                         iso-C.sub.3 H.sub.7                                                                        H          iso-C.sub.3 H.sub.7                                                                        96° /                                                                        1.5                                                                     0.35 mm.                    iso-C.sub.3 H.sub.7                                                                        cycloC.sub.6 H.sub.11                                                                      CH.sub.3   CH.sub.3     82-85° /                                                                     3                                                                       0.5 mm.                     iso-C.sub.4 H.sub.9                                                                        iso-C.sub.4 H.sub.9                                                                        CH.sub.3   CH.sub.3     63-65° /                                                                     3                                                                       0.5 mm                      iso-C.sub.4 H.sub.9                                                                        (CH.sub.3).sub.2 CHCH(CH.sub.3)                                                            H          C.sub.2 H.sub.5                                                                            100-106°                                                                     1.5                                                                     0.4 mm                      iso-C.sub.4 H.sub.9                                                                        iso-C.sub.4 H.sub.9                                                                        H          C.sub.2 H.sub.5                                                                            99-103° /                                                                    10                                                                      0.2 mm                      CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                     H          C.sub.2 H.sub.5                                                                            91-3°                                                                        10                                                                      (mp)                        H            (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                               H          C.sub.2 H.sub.5                                                                            100° /                                                                       8                                                                       0.2 mm                                                                        (sublimed)                  cycloC.sub.6 H.sub.11                                                                      iso-C.sub.3 H.sub.7                                                                        H          C.sub.2 H.sub.5                                                                            104-5° (mp)                                                                  8                     CH(CH.sub.3)CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              "          "            100-3° /                                                                     10                                                                      0.6 mm                      n-C.sub.4 H.sub.9                                                                          t-C.sub.4 H.sub.9                                                                          iso-C.sub.3 H.sub.7                                                                      H            81-4° /                                                                      6                                                                       0.5 mm                      H            (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                               C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                            98-100° /                                                                    20                                                                      1.0 mm                      CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                     H          iso-C.sub.3 H.sub.7                                                                        110-2° /                                                                     11                                                                      0.5 mm                      cycloC.sub.6 H.sub.11                                                                      iso-C.sub.3 H.sub.7                                                                        "          "            125-7° /                                                                     12                                                                      0.5 mm                      H            (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                               "          "            136-9° /                                                                     10                                                                      0.5 mm                      iso-C.sub.4 H.sub.9                                                                        iso-C.sub.4 H.sub.9                                                                        H          n-C.sub.3 H.sub. 7                                                                         108-9° /                                                                     20                                                                      0.3 mm                      CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                     "          n-C.sub.4 H.sub.9                                                                          129-31° /                                                                    30                                                                      0.4 mm                      CH(CH.sub.3)CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              "          "            112-4° /                                                                     30                                                                      0.1 mm                      CH(CH.sub.3)CH(C.sub.2 H.sub.5)CH(CH.sub.3)CH.sub.2                                                     "          n-C.sub.3 H.sub.7                                                                          *     20                    sec-C.sub.4 H.sub.9                                                                        seo-C.sub.4 H.sub.9                                                                        "          C.sub.2 H.sub.5 OCOCH.sub.2                                                                *     12                    "            "            "          HOCH.sub.2 CH.sub.2 CH.sub.2                                                               *     10                    "            "            "          H            68-71°                                                                       20                                                                      (mp)                        CH.sub.2 (CH.sub.2).sub.6 CH.sub.2                                                                      "          iso-C.sub.3 H.sub.7                                                                        100-110°                                                                     7                                                                       0.01 mm                     C.sub.2 H.sub.5                                                                            CH(CH.sub.3).sub.2 CH.sub.2 CH(CH.sub.3)                                                   "          "            80-81° /                                                                     7                                                                       (mp)                        H            CH(iso-C.sub.3 H.sub.7).sub.2                                                              "          n-C.sub.3 H.sub.7                                                                          83-86° /                                                                     15                                                                      (mp)                        CH.sub.2 CH.sub.2 CH(CH.sub.3)CH.sub.2 CH.sub.2 CH(isoC.sub.3 H.sub.7)                                  "          C.sub.2 H.sub.5                                                                            106-10° /                                                                    4                                                                       0.1 mm                      iso-C.sub.3 H.sub.7                                                                        (cyclo C.sub.7 H.sub.13)CH.sub.2                                                           "          "            122-6° /                                                                     20                                                                      0.005 mm                    CH(CH.sub.3).sub.2 CH.sub.2 CH(CH.sub.3)                                                   CH(CH.sub.3).sub.2 CH.sub.2 CH(CH.sub.3)                                                   H          C.sub.2 H.sub.5                                                                            88-90° /                                                                     20                                                                      0.001 mm                    sec.-C.sub.4 H.sub.9                                                                       iso-C.sub.4 H.sub.9                                                                        "          isoC.sub.3 H.sub.7                                                                         57-60°                                                                       2                                                                       (mp)                        C.sub.2 H.sub.5                                                                            CH(CH.sub.3).sub.2 CH(CH.sub.3)                                                            "          "            47-50°                                                                       8                                                                       (mp)                        n-C.sub.3 H.sub.7                                                                          CH(C.sub.2 H.sub.5).sub.2                                                                  "          C.sub.2 H.sub. 5                                                                           81-3° /                                                                      4                                                                       0.005 mm                    cycloC.sub.5 H.sub.9                                                                       iso-C.sub.4 H.sub.9                                                                        "          "            108-10° /                                                                    3                                                                       0.005 mm                    sec.C.sub.4 H.sub.9                                                                        (cyclo C.sub.6 H.sub.11)CH.sub.2                                                           "          "            106-9° /                                                                     20                                                                      0.005 mm                    n-C.sub.3 H.sub.7                                                                          (1'-methylcyclo                                                                            "          "            112-4° /                                                                     15                                 C.sub.6 H.sub.10)CH.sub.2            0.005 mm                    cycloC.sub.5 H.sub.9                                                                       CH.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                    "          n-C.sub.3 H.sub.7                                                                          120-1° /                                                                     8                                                                       0.6 mm                      (iso-C.sub.3 H.sub.7).sub.2 CH                                                             (Cyclo-C.sub.3 H.sub.5)CH.sub.2                                                            "          C.sub.2 H.sub.5                                                                            95-110° /                                                                    5                                                                       0.01 mm                     C.sub.2 H.sub.5                                                                            (CH.sub.3).sub.2 CHCH(CH.sub.3)                                                            "          HO(CH.sub.2).sub.6                                                                         --    20                    "            "            n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                          64-6° /                                                                      5                                                                       0.01 mm                     C.sub.2 H.sub.5                                                                            CH.sub.3).sub.2 CHCH(CH.sub.3)                                                             CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                                  64-5° /                                                                      1                                                                       0.005 mm                    "            "            CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                                   75-6° /                                                                      0.5                                                                     0.005 mm                    H            CH.sub.3 CH.sub.2 C(CH.sub.3).sub.2                                                        H          iso-C.sub.3 H.sub.7                                                                        170-2°                                                                       10                                                                      (mp)                        C.sub.2 H.sub.5                                                                            (C.sub.2 H.sub.5).sub.2 CH                                                                 "          "            64-6°                                                                        3                                                                       (mp)                        "            "            "          Cyclo-C.sub.3 H.sub.5                                                                      89-91° /                                                                     0.4                                                                     0.02 mm                     "            "            "          n-C.sub.6 H.sub.13                                                                         118-9° /                                                                     3                                                                       0.005 mm                    "            "            CH.sub.3   HOCH.sub.2 CH.sub.2                                                                        88-92° /                                                                     6                                                                       0.01 mm                     iso-C.sub.4 H.sub.9                                                                        sec.C.sub.4 H.sub.9                                                                        H          (cyclo-C.sub.5 H.sub.9)CH.sub.2                                                            124-7° /                                                                     3                                                                       0.3 mm                      "            "            "          (3'-methyl)CycloC.sub.5 H.sub.8                                                            106-110°                                                                     10                                                                      0.45 mm                     iso-C.sub.3 H.sub.7                                                                        iso-C.sub.3 H.sub.7                                                                        "          cycloC.sub.6 H.sub.11                                                                      94-5°                                                                        8                                                                       (mp)                        Sec.C.sub.4 H.sub.9                                                                        Sec-C.sub.4 H.sub.9                                                                        H          CycloC.sub.6 H.sub.11                                                                      80-81°                                                                       10                                                                      (mp)                        __________________________________________________________________________     * Compounds not distilled, but were tested in a crude state.             

                                      Table II                                    __________________________________________________________________________     ##STR7##                                                                                                                   Activity                        Compound                                      bp or                            R.sub.1            R.sub.2         R.sub.3   mp (° C)                                                                         μg                 __________________________________________________________________________    sec-C.sub.4 H.sub.9                                                                              sec-C.sub.4 H.sub.9                                                                           C.sub.2 H.sub.5                                                                          65-6° /0.2                                                                       2m                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              "          77° /0.5                                                                         3m                    H                  (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                                  "          88-100° /0.5                                                                     5m                                                                  (sublimed)                      sec-C.sub.4 H.sub.9                                                                              sec-C.sub.4 H.sub.9                                                                           n-C.sub.4 H.sub.9                                                                        75-6° /0.18                                                                      4m                    "                  "               CH.sub.3   53-6° /0.1                                                                       2m                    iso-C.sub.4 H.sub.9                                                                              (CH.sub.3).sub.2 CHCH(CH.sub.3)                                                               "          68-72° /0.5                                                                      2m                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              t-C.sub.4 H.sub.9                                                                        123-4° /12                                                                       2m                    H                  (CH.sub. 3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                                 iso-C.sub.3 H.sub.7                                                                      93-5° (mp)                                                                       2                     sec-C.sub.4 H.sub.9                                                                              sec-C.sub.4 H.sub.9                                                                           "          61-2° /0.01                                                                      5m                    n-C.sub.5 H.sub.11 iso-C.sub.3 H.sub.7                                                                           C.sub.2 H.sub.5                                                                          68° /0.35                                                                        3m                    cycloC.sub.6 H.sub.11                                                                            iso-C.sub.3 H.sub.7                                                                           CH.sub.3   131-3° /12                                                                       8m                    sec-C.sub.4 H.sub.9                                                                              sec-C.sub.4 H.sub.9                                                                           iso-C.sub.3 H.sub.7                                                                      111-2° /11                                                                       6m                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              "          134-8° /12                                                                       6m                    iso-C.sub.3 H.sub.7                                                                              iso-C.sub.3 H.sub.7                                                                           C.sub.2 H.sub.5                                                                          42-6° /0.02                                                                      8m                    H                  (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                                  iso-C.sub.4 H.sub.9                                                                      80-90° /0.5                                                                      7m                                                                  (Sublimed)                      "                  "               t-C.sub.4 H.sub.9                                                                        83-5° /mp.                                                                       5                     "                  "               H          81-7° /0.3                                                                       8m                    n-C.sub.4 H.sub.9  t-C.sub.4 H.sub.9                                                                             C.sub.2 H.sub.5                                                                          62- 4° /0.2                                                                      6m                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                                       iso-C.sub.3 H.sub.7                                                                      46-8° /0.01                                                                      6m                    iso-C.sub.4 H.sub.9                                                                              iso-C.sub.4 H.sub.9                                                                           C.sub.2 H.sub.5                                                                          65-7° /0.15                                                                      12                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              n-C.sub.4 H.sub.9                                                                        81-5° /0.35                                                                      12                    "                                  H          59-63° /0.2                                                                      11                    H                  (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                                  n-C.sub.4 H.sub.9                                                                        92° /0.15                                                                        20                    H                  C.sub.2 H.sub.5 CH(CH.sub.3)CH.sub.2 CH(CH.sub.3)                                             C.sub.2 H.sub.5                                                                          146-7° /15                                                                       18                    iso-C.sub.3 H.sub.7                                                                              cycloC.sub.6 H.sub.11                                                                         n-C.sub.3 H.sub.7                                                                        69-73° /.003                                                                     11                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              CH.sub.3   71-4° /0.5                                                                       25                    n-C.sub.4 H.sub.9  t-C.sub.4 H.sub.9                                                                             iso-C.sub.4 H.sub.9                                                                      75-6° /0.2                                                                       40                    sec-C.sub.4 H.sub.9                                                                              sec-C.sub. 4 H.sub.9                                                                          H          56-8° /0.2                                                                       10                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              iso-C.sub.4 H.sub.9                                                                      81-6° /0.2                                                                       6m                    sec.-C.sub.4 H.sub.9                                                                             iso-C.sub.4 H.sub.9                                                                           n-C.sub.3 H.sub.7                                                                        60;20  /0.002                                                                           2m                    "                  "               H          70-2° /2.0                                                                       4m                    C.sub.2 H.sub.5    CH(CH.sub.3).sub.2 CH(CH.sub.3)                                                               iso-C.sub.3 H.sub.7                                                                      *         2                     n-C.sub.3 H.sub.7  (C.sub.2 H.sub.5).sub.2 CH                                                                    C.sub.2 H.sub.5                                                                          60-2° /0.02                                                                      5m                    cycloC.sub.5 H.sub.9                                                                             iso-C.sub.4 H.sub.9                                                                           "          89° /0.5                                                                         6m                    sec-C.sub.4 H.sub.9                                                                              (cyclo-C.sub.6 H.sub.11)CH.sub.2                                                              CH.sub.3   72-4° /0.003                                                                     15                    CH.sub.3           (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                                  C.sub.2 H.sub.5                                                                          55-7° /0.01                                                                      3m                    sec.C.sub.4 H.sub.9                                                                              cycloC.sub.7 H.sub.13                                                                         "          83-5° /0.02                                                                      9m                    (isoC.sub.3 H.sub.7).sub.2 CH                                                                    (cycloC.sub.3 H.sub.5)CH.sub.2                                                                cyclo-C.sub.4 H.sub.7                                                                    88- 92° /0.005                                                                   6m                    iso-C.sub.20 H.sub.7                                                                             iso-C.sub.4 H.sub.9                                                                           n-C.sub.6 H.sub.13                                                                       90-2° /0.2                                                                       4m                    H                  (CH.sub.3).sub.2 CH(CH.sub.2).sub.3 CH(CH.sub.3)                                              "          136-41° /0.2                                                                     20                    C.sub.2 H.sub.5    (CH.sub.3).sub.2 CHCH(CH.sub.3)                                                               HO(CH.sub.2).sub.5                                                                       120-6° /0.01                                                                     8m                    iso-C.sub.3 H.sub.7                                                                              iso-C.sub.3 H.sub.7                                                                           C.sub.2 HOOC(CH.sub.                                                                     104-9° /0.01                                                                     4m                    "                  "               HOOC(CH.sub.2).sub.4                                                                     150-70° /0.7                                                                     30                    C.sub.2 H.sub.5    CH(CH.sub.3).sub.2 CH.sub.2 CH(CH.sub.3)                                                      C.sub.2 H.sub.5                                                                          52-3° /0.01                                                                      2m                    sec.C.sub.4 H.sub.9                                                                              sec.-C.sub.4 H.sub.9                                                                          cyclo C.sub.6 H.sub.11                                                                   86-7° /0.005                                                                     9m                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              "          120-6° /0.01                                                                     15                    H                  (isoC.sub.3 H.sub.7).sub.2 CH                                                                 iso C.sub.3 H.sub.7                                                                      130-1° /m.p.                                                                     3                     H                  (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                                  cyclo C.sub.6 H.sub.11                                                                   114-6° /m.p.                                                                     40                    CH.sub.2 CH.sub.2 CH(CH.sub.3)CH.sub.2 CH.sub.2 CH(iso C.sub.3 H.sub.7)-                                         CH.sub.3   73-4° /0.15                                                                      3m                    C.sub.2 H.sub.5    CH(CH.sub.3).sub.2 CH(CH.sub.3)                                                               C.sub.2 H.sub.5 OOC(CH.sub.2)                                                            107-8° /0.001                                                                    20                    iso-C.sub.3 H.sub.7                                                                              (cyclo C.sub.7 H.sub.13)CH.sub.2                                                              C.sub.2 H.sub.5                                                                          106-8° /0.5                                                                      20                    sec. C.sub.4 H.sub.9                                                                             sec.C.sub.4 H.sub.9                                                                           (CH.sub.3).sub.3 CCH.sub.2                                                               74-75° /0.3                                                                      5m                    C.sub.2 H.sub.5    CH(CH.sub.3).sub.2 CH(CH.sub.3)                                                               "          68-9° /0.4                                                                       6m                    iso-C.sub.4 H.sub.9                                                                              "               cyclo C.sub.3 H.sub.5                                                                    70° /0.2                                                                         4m                    n-C.sub.3 H.sub.7  (C.sub.2 H.sub.5).sub.2 CH                                                                    cyclo C.sub.4 H.sub.7                                                                    78.5-80° /0.1                                                                    4m                    C.sub.2 H.sub.5    iso C.sub.4 H.sub.9                                                                           "          63-4° /0.2                                                                       3m                    CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                              cyclo C.sub.3 H.sub.5                                                                    77-82° /0.2                                                                      2m                    "                                  cyclo C.sub.4 H.sub.7                                                                    80° /0.25                                                                        2m                    "                                  cyclo C.sub.5 H.sub.9                                                                    103-7° /0.6                                                                      5m                    iso C.sub.3 H.sub.7                                                                              iso C.sub.4 H.sub.9                                                                           cyclo C.sub.3 H.sub.5                                                                    55° /0.005                                                                       2m                    "                  "               cyclo C.sub.5 H.sub.9                                                                    101-3° /2                                                                        3m                    CH.sub.2 (CH.sub.2).sub.6 CH.sub.2 C.sub.2 H.sub.5                                                                          59° /0.005                                                                       7m                    sec. C.sub.4 H.sub.9                                                                             (cyclo C.sub.3 H.sub.5)CH.sub.2                                                               "          58-9° /0.01                                                                      3m                    (CH.sub.3).sub.2 CHCH.sub.2 CH(CH.sub.3)                                                         (CH.sub.3).sub.2 CHCH.sub.2 CH(CH.sub.3)                                                      CH.sub.3   58-9° /0.01                                                                      10                    H                  (iso C.sub.3 H.sub.7).sub.2 CH                                                                cyclo C.sub.3 H.sub.5                                                                    136-8° /mp.                                                                      4                     __________________________________________________________________________     * Not distilled, tested crude.                                           

                                      Table III                                   __________________________________________________________________________     ##STR8##                                                                     Compound                               Activity                                R.sub.1                                                                          R.sub.2                       R.sub.4                                                                             b.p. ° C                                                                       μg                         __________________________________________________________________________    sec-C.sub.4 H.sub.9 sec-C.sub.4 H.sub.9                                                                        CH.sub.3                                                                            90-3° /0.7                                                                      1m                            iso-C.sub.3 H.sub.7 iso-C.sub.3 H.sub.7                                                                        C.sub.2 H.sub.5                                                                     84-6° /0.3                                                                      8m                            CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                            "     98-100° /0.3                                                                    7m                            C.sub.2 H.sub.5     (CH.sub.3).sub.2 CHCH(CH.sub.3)                                                            "     93-4° /0.4                                                                      8m                            CH(CH.sub.3)CH(C.sub.2 H.sub.5)CH(CH.sub.3)CH.sub.2                                                            "     106-7° /0.4                                                                     6m                            iso-C.sub.3 H.sub.7 cycloC.sub.6 H.sub.11                                                                      "     109-115° /0.3                                                                   10                            H                   (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                               "     115-8° /0.3                                                                     20                            CH.sub.2 CH(C.sub.2 H.sub.5)CH.sub.2 CH.sub.2 CH(CH.sub.                                                       CH.sub.3                                                                            107-9° /0.3                                                                     15                            iso-C.sub.3 H.sub.7 iso-C.sub.4 H.sub.9                                                                        n-C.sub. 3 H.sub.7                                                                  74-6° /0.005                                                                    9m                            C.sub.2 H.sub.5     iso-C.sub.4 H.sub.9                                                                        n-C.sub.5 H.sub.11                                                                  95-8° /0.15                                                                     9m                            __________________________________________________________________________

Utility

The cold receptor stimulants used in this invention find utility in awide variety of consumer products for consumption by or application tothe human body. Broadly speaking, these products can be divided intoingestibles and topicals, both terms being taken in their broadestpossible sense. Thus ingestible is to be taken as including not onlyfoodstuffs and beverages taken into the mouth and swallowed, but alsoother orally ingested products taken for reasons other than theirnutritional value, e.g. indigestion tablets, antacid preparations,laxatives, etc. Ingestible is also to be taken to include ediblecompositions taken by mouth, but not necessarily swallowed, e.g. chewinggum. Topical is to be taken as including not only compositions such asperfumes, powders and other toiletries, lotions, liniments, oils andointments, applied to the external surfaces of the human body, whetherfor medical or other reasons, but also compositions applied to, orwhich, in normal usage, come in contact with, internal mucous membranesof the body, such as those of the nose, mouth, or throat, whether bydirect or indirect application, mouthwash and gargle compositions.Topical products, in this context, also include toilet articles such ascleansing tissues and toothpicks.

In formulating the products of this invention the cold receptorstimulants will be incorporated into a vehicle by means of which thecompound may be applied to the person. The vehicle may, itself becompletely insert or it may, and usually will, contain other activeingredients. A wide variety of vehicles will be suitable, depending uponthe particular product involved, such vehicles including solids,liquids, emulsions, foams and gels. Typical vehicles for the coldreceptor stimulants include aqueous or alcoholic solutions, oils andfats such as hydrocarbon oils, fatty acid esters, long chain alcoholsand silicone oils; finely divided solids such as starch or talc;cellulosic materials such as paper tissue; low-boiling hydrocarbons andhalohydrocarbons used as aerosol propellants; gums and natural orsynthetic resins.

Generally, these vehicles will contain at least one or more of thefollowing adjuvants: flavourants, colourants, perfuming agents, surfaceactive agents, antiseptic agents, such as are usually employed intopical and ingestible compositions.

A more detailed discussion of particular products according to thisinvention follows.

Toiletries and Cosmetics

A major area of utility of the cold receptor stimulants of thisinvention will be in the field of toilet preparations broadly classed aspersonal care products. These may be defined as manufactured productsapplied to the person for the purposes of grooming or hygiene or forcosmetic purposes, including make up and perfumery, but excludingethical and proprietary medical preparations. Particular personal careproducts are discussed hereinafter by way of example and are illustratedhereinafter in the specific examples.

One class of personal care product into which the compounds of thisinvention may be incorporated is represented by lotions for topicalapplication, e.g. aftershave lotions, toilet water etc. where thecompound will be used in alcoholic or aqueous alcoholic solution, suchsolutions usually also containing a perfume or mild antiseptic or both.The amount of compound added to the formulation will usually be in therange 0.1 to 2.5% by weight based on the total composition.

Another class of personal care product is represented by soap andsoap-based compositions where the compounds will be used in combinationwith an oil or fat or a natural or synthetic surfactant e.g. a fattyacid salt or a laurylsulphate salt, the composition usually alsocontaining an essential oil or perfume. The range of soap compositionswill include soaps of all kinds e.g. toilet soaps, shaving soaps,shaving foams etc. particularly shaving foams of the aerosol type.Usually the compound will be added to the formulation in amount of from0.5 to 2.5% by weight.

A further class of personal care products into which the cold receptorstimulants may be incorporated is represented by cosmetic creams,emollients and lotions, such creams, emollients and lotions usuallycomprising an oil-in-water emulsion as a base and optionally containinga range of other ingredients such as wax, preservative, perfume,antiseptics, astringents, pigments etc. Also included within this classare lipstick compositions, such compositions usually comprising an oiland wax base into which the coolant can be incorporated along with otheringredients e.g. pigments. Once again the formulation of such products,apart from the incorporation of the cold receptor stimulant, usually inan amount by weight of from 0.1 to 2.5%.

Personal care products for oral hygiene into which the cold receptorstimulants of this invention can be incorporated include mouthwash,gargle and dentifrice compositions. The first two may be consideredtogether and will usually comprise an aqueous, alcoholic oraqueous-alcoholic solution of an antiseptic often coloured of flavouredfor palatability, to which the cold receptor stimulant is added in anamount of from 0.01 to 1.0% by weight.

Dentifrice compositions may be of the solid block, powder, paste orliquid type and will usually comprise a finely divided abrasive orpolishing material, e.g. precipitated chalk, silica, magnesium silicate,aluminium hydroxide or other similar materials well known in the art,and a detergent of foaming agent. Optional ingredients which may also beincluded are flavouring agents and colourants, antiseptics, lubricants,thickeners, emulsifiers or plasticizers. The amount of cold receptorstimulant added in such compositions will generally be from 0.1 to 2.0%by weight based on the total composition.

Edible and Potable Compositions

The cold receptor stimulants of this invention may be incorporated intoa wide range of edible and potable compositions comprising an edible orpotable base and usually one or more flavouring or colouring agents. Theparticular effect of the cold receptor stimulant is to create a cool orfresh sensation in the mouth, and in some cases, even in the stomach,and therefore the compounds find particular utility in sugar-basedconfectionery such as chocolate, boiled sweets, mints and candy, in icecream and jellies and in chewing gum. The formulation of suchconfections will be by traditional techniques and according toconventional recipes and as such forms no part of this invention. Thecold receptor stimulant will be added to the recipe at a convenientpoint and in amount sufficient to produce the desired cooling effect inthe final product. As already indicated, the amount will vary dependingupon the particular compound, the degree of cooling effect desired andthe strength of other flavourants in the recipe. For general guidance,however, amounts in the range 0.01 to 1.0% by weight based on the totalcomposition will be found suitable.

Similar considerations apply to the formulation of beverages. Generallyspeaking the compounds will find most utility in soft drinks, e.g. fruitsquashes, lemonade, cola etc., but may also be used in alcoholicbeverages. The amount of compound used will generally be in the range0.01 to 1.0% by weight based on the total composition.

Medicaments

Because of their cooling effect on the skin and on the mucous membranesof the mouth, throat and nose and of the gastrointestinal tract the coldreceptor stimulants may be used in a variety of oral medicines, nasaland throat sprays, and topical compositions, particularly where acounter-irritant is required. Generally speaking, these medicalpreparations, whether topical or ingestible, proprietary or ethical,will contain a pharmaceutically acceptable carrier, either liquid orsolid, a pharmaceutically active ingredient and into these preparationsthe cold receptor stimulants of this invention can readily beincorporated to provide a pleasant cooling effect on the skin, or othersurface tissues of the body, or in the mouth or gastrointestinal tractdepending on particular preparation and whether it is to be appliedexternally or internally. A particular utility for the compounds of thisinvention is in the formulation of antacid and indigestion remedies, andespecially those based on sodium bicarbonate, magnesium oxide, calciumor magnesium carbonate, aluminum or magnesium hydroxide or magnesiumtrisilicate. In such compositions the compound will usually be added inan amount of from 0.1 to 2.0%.

The cold receptor stimulants may also be included in oral analgesiccompositions, e.g. with acetyl salicyclic acid or its salts, and innasal decongestants e.g. those containing ephedrine.

Consumer products according to the invention are illustrated by thefollowing Examples in which all percentages are by weight.

EXAMPLE 1 After-Shave Lotion

An after-shave lotion was prepared according to the following recipe bydissolution of the ingredients in the liquid and cooling and filtering:

    ______________________________________                                        Denatured ethanol      75%                                                    Diethylphthalate       1.0%                                                   Propylene Glycol       1.0%                                                   Lactic Acid            1.0%                                                   Perfume                3.0%                                                   Water                  to 100%                                                ______________________________________                                    

Into the base lotion was added 0.5% by weight ofN-ethyl-N',N'-di-sec-butyl urea.

When the final solution was applied to the face a clearly noticeablecooling effect became apparent after a short interval of time.

EXAMPLE 2 Antiseptic Ointment

An ointment was prepared according to the following formulation:

    ______________________________________                                        Cetyltrimethyl ammonium 4.0%                                                    bromide                                                                     Cetyl Alcohol           6.0%                                                  Stearyl Alcohol         6.0%                                                  White Paraffin          14.0%                                                 Mineral Oil             21.0%                                                 Water                   to 100%                                               ______________________________________                                    

The ingredients were mixed, warmed to 40° C. and emulsified in a highspeed blender. Added to the mixture during blending was 1.5% ofN,N-dimethyl-N'-cyclohexyl-N'-isopropyl urea.

The final ointment when applied to the skin gave rise to a coolingeffect.

EXAMPLE 3

Cleansing Tissue

A cleansing liquid was prepared having the formulation:

    ______________________________________                                        Triethanolamine Lauryl 1.0%                                                     sulphate                                                                    Glycerol               2.0%                                                   Perfume                .95%                                                   Water                  to 100%                                                ______________________________________                                    

To this liquid was added 1.0% of N-ethyl-N'-n-butyl-N'-t-butyl urea. Apaper tissue was then soaked in the liquid.

When the impregnated tissue was used to wipe the skin a fresh coolsensation developed on the skin after a short interval.

EXAMPLE 4 Toothpaste

The following ingredients were mixed in a blender:

    ______________________________________                                        Dicalcium phosphate      48.0%                                                Sodium lauryl sulphate   2.5%                                                 Glycerol                 24.8%                                                Sodium carboxymethyl cellulose                                                                         2.0%                                                 Citrus flavourant        1.0%                                                 Sodium saccharin         0.5%                                                 Water                    to 100%                                              ______________________________________                                    

Shortly before completion of the blending operation 1.0% by weight ofN-(2,2-dimethylpropionyl)-2,6-dimethylpiperidine was added to theblender.

When applied as a toothpaste a pleasant cooling effect is noticed in themouth.

EXAMPLE 5 Aerosol Shaving Soap

An aerosol shaving soap composition was formulated according to thefollowing recipe:

    ______________________________________                                        Stearic Acid           6.3%                                                   Lauric Acid            2.7%                                                   Triethanolamine        4.6%                                                   Sodium Carboxymethyl   0.1%                                                    Cellulose                                                                    Sorbitol               5.0%                                                   Water                  to 100%                                                Perfume                0.5%                                                   ______________________________________                                    

The composition was prepared by fusing the acids in water, adding thetriethanolamine, cooling and adding the other constituents. To themixture was then added 0.5% of N,N-di-sec-butyl propionamide.

The composition was then packaged in an aerosol dispenser under pressureof a butane propellant.

When used in shaving a fresh cool sensation was noticed on the face.

EXAMPLE 6 Soft Drink

A soft drink concentrate was prepared from the following recipe:

    ______________________________________                                        Pure orange juice    60%                                                      Sucrose              10%                                                      Saccharin            0.2%                                                     Orange flavouring    0.1%                                                     Citric acid          0.2%                                                     Sulphur dioxide      trace amount                                             Water                to 100%                                                  ______________________________________                                    

To the concentrate was added 0.10% of N-(2,4,4trimethylpent-2-yl)-2-methylpropionamide.

The concentrate was diluted with water and tasted. An orange flavourhaving a pleasantly cool after-effect was obtained.

EXAMPLE 7 Toothpick

The tip of a wooden toothpick was impregnated with an alcoholic solutioncontaining N,N-di-sec-butyl methanesulphonamide in an amount sufficientto deposit on the toothpick 0.05 mg. of the compound. The toothpick wasthen dried.

When placed against the tongue a cool sensation is noticed after a shortperiod of time.

EXAMPLE 8 After Shave Lotion

An after shave lotion was prepared according to the following recipe bydissolution of the ingredients in the liquid and cooling and filtering:

    ______________________________________                                        Denatured ethanol      75%                                                    Diethylphthalate       1.0%                                                   Propylene Glycol       1.0%                                                   Lactic Acid            1.0%                                                   Perfume                3.0%                                                   Water                  to 100%                                                ______________________________________                                    

Into a sample of the base lotion was added 0.7% by weight based on theweight of the sample of N-propionyl-2,6-dimethylpiperidine.

When the final solution was applied to the face a clearly noticeablecooling effect became apparent after a short interval of time.

EXAMPLE 9 Cleansing Tissue

A cleansing liquid was prepared having the formulation:

    ______________________________________                                        Triethanolamine lauryl 1.0%                                                     sulphate                                                                    Glycerol               2.0%                                                   Perfume                .95%                                                   Water                  to 100%                                                ______________________________________                                    

To this liquid was added 1% of N-isobutyl-N-sec.butyl butanamide. Apaper tissue was then soaked in the liquid.

When the impregnated tissue was used to wipe the skin a fresh coolsensation developed on the skin after a short interval.

EXAMPLE 10 Toothpaste

The following ingredients were mixed in a blender:

    ______________________________________                                        Dicalcium phosphate    48.0%                                                  Sodium lauryl sulphate 2.5%                                                   Glycerol               24.8%                                                  Sodium carboxymethyl   2.0%                                                     cellulose                                                                   Citrus flavourant      1.0%                                                   Sodium saccharin       0.5%                                                   Water                  to 100%                                                ______________________________________                                    

Shortly before completion of the blending operation 1% by weight ofN-n-pentyl-(N,N')diisopropylurea was added to the blender.

When applied as a toothpaste a pleasant cooling effect is noticed in themouth.

EXAMPLE 11 Aerosol Shaving Soap

An aerosol shaving soap composition was formulated according to thefollowing recipe:

    ______________________________________                                        Stearic acid           6.3%                                                   Lauric acid            2.7%                                                   Triethanolamine        4.6%                                                   Sodium carboxymethyl   0.1%                                                     cellulose                                                                   Sorbitol               5.0%                                                   Water                  to 100%                                                Perfume                0.5%                                                   ______________________________________                                    

The composition was prepared by fusing the acids in water, adding thetriethanolamine, cooling and adding the other constituents. To themixture was then added 0.7% ofN-isobutyl-N'-ethyl-N-(1,2-dimethyl-n-propyl)urea. The composition wasthen packaged in an aerosol dispenser under pressure of a butanepropellant.

EXAMPLE 12 Toothpaste

The following ingredients were mixed in a blender:

    ______________________________________                                        Dicalcium phosphate    48.0%                                                  Sodium lauryl sulphate 2.5%                                                   Glycerol               24.8%                                                  Sodium carboxymethyl   2.0%                                                     cellulose                                                                   Citrus flavourant      1.0%                                                   Sodium saccharin       0.5%                                                   Water                  to 100%                                                ______________________________________                                    

Shortly before completion of the blending operation 1.5% by weight ofN,N-diisopropyl ethanesulphonamide was added to the blender.

When applied as a toothpaste a pleasant cooling effect is noticed in themouth.

EXAMPLE 13 Aerosol Shaving Soap

An aerosol shaving soap composition was formulated according to thefollowing recipe:

    ______________________________________                                        Stearic acid           6.3%                                                   Lauric acid            2.7% -Triethanolamine 4.6%                             Sodium carboxymethyl   0.1%                                                     cellulose                                                                   Sorbitol               5.0%                                                   Water                  to 100%                                                Perfume                0.5%                                                   ______________________________________                                    

The composition was prepared by fusing the acids in water, adding thetriethanolamine, cooling and adding the other constituents. To themixture was then added 1.0% of N-isobutyl-N-isopropylpropanesulphonamide. The composition was then packaged in an aerosoldispenser under pressure of a butane propellant.

When used in shaving a fresh cool sensation is distinctly noticeable onthe face.

EXAMPLE 14 Hair Shampoo

Sodium lauryl ether sulphate, 10 g., was dispersed in 90 g. water in ahigh speed mill. To the dispersion was added 2% by weight ofN-n-butyl-N,N'-di-sec.butylurea. When the hair is washed using theshampoo a fresh, cool sensation is noticed on the scalp.

EXAMPLE 15 Toothpick

The tip of a wooden toothpick was impregnated with an alcoholic solutioncontaining N'-[N-ethyl-N-(1,2-dimethyl-n-propyl)carbamoyl]pyrrolidine,in an amount sufficient to deposit on the toothpick 0.05 mg. of thecompound. The toothpick was then dried.

When placed against the tongue a cool sensation is noticed after a shortperiod of time.

EXAMPLE 16 Soft Drink

A soft drink concentrate was prepared from the following recipe:

    ______________________________________                                        Pure orange juice    60%                                                      Sucrose              10%                                                      Saccharin            0.2%                                                     Orange flavouring    0.1%                                                     Citric acid          0.2%                                                     Sulphur dioxide      Trace amount                                             Water                to 100 %                                                 ______________________________________                                    

To the concentrate was added 0.2% of N,N-di-sec. butylethanesulphonamide.

The concentrate was diluted with water and tasted. An orange flavourhaving a pleasantly cool after-effect was obtained.

EXAMPLE 17 Toilet Water

A toilet water was prepared according to the following recipe:

    ______________________________________                                        Denatured ethanol      75.0%                                                  Perfume                5.0%                                                   Water                  to 100%                                                ______________________________________                                    

To the recipe was added 2.0% based on the total composition, ofN,N-di-sec.butyl methanesulphonamide.

As with the after-shave lotions, a cooling effect was clearly noticeableon the skin well after the termination of any cooling effectattributable to the evaporation of the alcoholic carrier.

EXAMPLE 18 Soft Sweet

Water was added to icing sugar at 40° C. to form a stiff paste. 0.2% ofN-n-propyl-N-(1-ethyl-n-propyl)-N'-cyclopropylurea was then stirred intothe paste and the mixture allowed to set. A soft sweet mass resultedhaving the characteristic cooling effect in the mouth of peppermint butwithout the minty flavour or odour.

EXAMPLE 19 Hydrophilic Ointment

A hydrophilic ointment was prepared having the following formulation:

    ______________________________________                                        Propylene Glycol       12%                                                    1-Octadecanol          25%                                                    White soft paraffin    25%                                                    Sodium lauryl sulphate  1%                                                    Water                  to 100%                                                ______________________________________                                    

The sodium lauryl sulphate was added to the water and heated to 60° C.The paraffin was melted by heating to 60° C. and was then added to thesodium lauryl sulphate mixture with stirring. Propylene glycol and1-octadecanol was then added to this mixture.

To the resultant mixture was added 1.5% of N-isobutyl-N-sec.butylformamide.

The final ointment when applied to the skin gave rise to a markedcooling effect.

EXAMPLE 20 Deodorant Composition

A deodorant composition suitable for formulation and dispensing as anaerosol under pressure of a suitable propellant was formulated accordingto the following recipe:

    ______________________________________                                        Denatured ethanol      96.9%                                                  Hexachlorophene        2.0%                                                   Isopropyl myristate    1.0%                                                   Perfume                0.1%                                                   ______________________________________                                    

To the composition was added 2% by weight ofN-isobutyl-N'-ethyl-N-cyclopentyl urea. Application of the finalcomposition gave rise to a definite cooling sensation on the skin.

EXAMPLE 21 Lipstick

1.0% by weight of N-ethyl-N-(1,2-dimethyl-n-propyl)-6-hydroxyhexanamidewas incorporated into a proprietary lipstick by melting the lipstick,adding the compound, and allowing the lipstick to resolidify. Whenapplied to the lips a persistent cooling effect is clearly noticeable.

EXAMPLE 22 Solid Cologne

A solid cologne was formulated according to the following recipe:

    ______________________________________                                        Denatured ethanol      74.5%                                                  Propylene glycol       3.0%                                                   Sodium stearate        5.0%                                                   Perfume                5.0%                                                   Water                  to 100%                                                ______________________________________                                    

The sodium stearate was dissolved by stirring in a warm mixture of theethanol, propylene glycol and water. To the solution was added theperfume and 2% of N-isopropyl-N-isobutyl cyclopentanecarboxamide, andthe mixture then allowed to solidify into a waxy cake.

When applied to the forehead a strong cooling effect is obtained.

EXAMPLE 23 Hair Tonic

A hair tonic was formulated containing:

    ______________________________________                                        Denatured ethanol      84.5%                                                  Castor oil             14.0%                                                  Resorcinol             0.5%                                                   Perfume                1.0%                                                   ______________________________________                                    

The castor oil, resorcinol and perfumes were dissolved in the ethanolcomponent and to the solution was added 2% ofN-ethanesulphonyl-2,6-dimethylpiperidine. When rubbed on the scalp acooling effect is noticed.

EXAMPLE 24 Mouthwash

A concentrated mouthwash composition was prepared according to thefollowing recipe:

    ______________________________________                                        Ethanol                3.0%                                                   Borax                  2.0%                                                   Sodium bicarbonate     1.0%                                                   Glycerol               10.0%                                                  Flavourant             0.4%                                                   Thymol                 0.03%                                                  Water                  to 100%                                                ______________________________________                                    

To the composition was added 0.1% ofN-methyl-N-2-hydroxyethyl-N'-n-propyl-N'-(1'-ethyl-n-propyl) urea.

When diluted with approximately 10 times its own volume of water andused to rinse the mouth a strong cooling effect is obtained in themouth.

EXAMPLE 25 Talcum Powder

A talcum powder was prepared by grinding together the following:

    ______________________________________                                        Low micron talc         90%                                                   Zinc stearate           5%                                                    Starch                  5%                                                    ______________________________________                                    

In the course of grinding there was added 1.0% ofN-sec.butyl-N-isobutyl-N'-isopropylurea. A talcum powder having afreshening and cooling effect was obtained.

EXAMPLE 26 Chewing Gum

Leaves of a proprietary chewing gum were leached in running water for168 hours to remove all water-soluble flavourants. At the end of theleaching operation the chewing gum base had no detectable minty odour orflavour. The chewing gum base was then kneaded with 0.5% ofN-[N'-ethyl-N'-(1,2-dimethyl-n-propyl)carbamoyl]morpholine. Whencompared with the water-extracted chewing gum base, the final productshowed no distinguishable change in flavour but showed a marked coolingeffect in the mouth.

EXAMPLE 27 Toilet Water

A toilet water was prepared according to the following recipe:

    ______________________________________                                        Denatured ethanol      75.0%                                                  Perfume                 5.0%                                                  Water                  to 100%                                                ______________________________________                                    

To the recipe was added 1.0% based on the total composition, ofN-[N'-ethyl-N'-(1,2-dimethyl-n-propyl)carbamoyl]pyrrolidine. As with theafter-shave lotion, a cooling effect was clearly noticeable on the skinwell after the termination of any cooling effect attributable to theevaporation of the alcoholic carrier.

EXAMPLE 28 Soft Sweet

Water was added to icing sugar at 40° C. to form a stiff paste. 0.2% ofN-cyclohexyl-N-isopropylacetamide was then stirred into the paste andthe mixture allowed to set. A soft sweet mass resulted having thecharacteristic cooling effect in the mouth of peppermint but without theminty flavour or odour.

EXAMPLE 29 Hydrophilic Ointment

A hydrophilic ointment was prepared having the following formulation:

    ______________________________________                                        Propylene Glycol       12%                                                    1-Octadecanol          25%                                                    White Soft Paraffin    25%                                                    Sodium lauryl sulphate  1%                                                    Water                  to 100 %                                               ______________________________________                                    

The sodium lauryl sulphate was added to the water and heated to 60° C.The paraffin was melted by heating to 60° C. and was then added to thesodium lauryl sulphate mixture with stirring. Propylene glycol and1-octadecanol was then added to this mixture.

To the resultant mixture was added 1.5% of N,N-di-sec.butylethanesulphonamide.

The final ointment when applied to the skin gave rise to a markedcooling effect.

EXAMPLE 30 Deodorant Composition

A deodorant composition suitable for formulation and dispensing as anaerosol under pressure of a suitable propellant was formulated accordingto the following recipe:

    ______________________________________                                        Denatured ethanol      96.9%                                                  Hexachlorophene        2.0%                                                   Isopropyl myristate    1.0%                                                   Perfume                0.1%                                                   ______________________________________                                    

To the composition was added 1% by weight of N,N-di-sec.butylmethanesulphonamide. Application of the final composition gave rise to adefinite cooling sensation on the skin.

EXAMPLE 31 Lipstick

1.0% by weight of N-isobutyl-N-sec.butyl-N'-cyclopentylurea wasincorporated into a proprietary lipstick by melting the lipstick, addingthe compound, and allowing the lipstick to resolidify. When applied tothe lips a persistent cooling effect is clearly noticeable.

EXAMPLE 32 Solid Cologne

A solid cologne was formulated according to the following recipe:

    ______________________________________                                        Denatured ethanol      74.5%                                                  Propylene glycol        3.0%                                                  Sodium stearate         5.0%                                                  Perfume                5.0%                                                   Water                  to 100 %                                               ______________________________________                                    

The sodium stearate was dissolved by stirring in a warm mixture of theethanol, propylene glycol and water. To the solution was added theperfume and 1.0% of N,N-diisobutyl-N',N'-dimethylurea, and the mixturethen allowed to solidify into a waxy cake.

When applied to the forehead a strong cooling effect is obtained.

EXAMPLE 33 Hair Tonic

A hair tonic was formulated containing:

    ______________________________________                                        Denatured ethanol      84.5%                                                  Castor Oil             14.0%                                                  Resorcinol             0.5%                                                   Perfume                1.0%                                                   ______________________________________                                    

The castor oil, resorcinol and perfumes were dissolved in the ethanolcomponent and to the solution was added 1.0% ofN-(2,2-dimethylpropionyl)-2,6-dimethylpiperidine. When rubbed on thescalp a cooling effect is noticed.

EXAMPLE 34 Mouthwash

A concentrated mouthwash composition was prepared according to thefollowing recipe:

    ______________________________________                                        Ethanol                3.0%                                                   Borax                  2.0%                                                   Sodium bicarbonate     1.0%                                                   Glycerol               10.0%                                                  Flavourant             0.4%                                                   Thymol                 0.03%                                                  ______________________________________                                    

To the composition was added 0.1% ofN-(2,4,4-trimethylpent-2-yl)-2-methylpropionamide. When diluted withapproximately 10 times its own volume of water and used to rinse themouth a strong cooling effect is obtained in the mouth.

EXAMPLE 35 Talcum Powder

A talcum powder was prepared by grinding together the following:

    ______________________________________                                        Low micron talc         90%                                                   Zinc stearate           5%                                                    Starch                  5%                                                    ______________________________________                                    

In the course of grinding there was added 2% ofN-(2,4-dimethylpent-3-yl)-2-methylpropionamide. A talcum powder having afreshening and cooling effect was obtained.

EXAMPLE 36 Chewing Gum

Leaves of a proprietary chewing gum were leached in running water for168 hours to remove all water-soluble flavourants. At the end of theleaching operation the chewing gum base had no detectable minty odour orflavour. The chewing gum base was then kneaded with 0.05% ofN-n-propyl-N-(1-ethyl-n-propyl)cyclobutanecarboxamide. When comparedwith the water-extracted chewing gum base, the final product showed nodistinguishable change in flavour but showed a marked cooling effect inthe mouth.

The above Examples illustrate the range of compounds and the range ofcompositions included within the present invention. However, they arenot to be taken as limiting the scope of the invention in any way.Numerous other compounds within the general formula will be equallysuitable for use in the compositions of Examples 1-36 and thephysiological cooling effect obtained with the compounds of theinvention will recommend their use in a wide variety of othercompositions where the cooling effect will be of value.

The substituted ureas, amides and sulphonamides hereinbefore referred toas cold receptor stimulants in ingestible and topical compositions alsofind utility as cold receptor stimulants in tobacco andtobacco-containing manufactures.

As has already been mentioned, menthol is extensively used for thispurpose notwithstanding its strong minty odour and relative volatility.Other similar compounds have also been proposed as alternatives tomenthol in tobacco, see for example, the various publicationshereinbefore referred to. Still other compounds have been proposed as`flavourants` in tobacco rather than `coolants` and amongst these may bementioned 2-isopropyl-5-methyl hexanol (alternatively named2,6-dimethylhept-3-yl methanol) and related compounds as disclosed inU.S. Pat. No. 3,704,714. Notwithstanding these various disclosures aneed still exists for alternatives to menthol for incorporating intotobacco to provide a `cool` effect when smoked.

It is a further object of the present invention, therefore, to providetobacco and tobacco-containing manufactures containing an ingredientwhich creates a `cool` sensation when the ingredient comes into contactwith the nasal and oral mucosa, either in the tobacco smoke, or bydirect contact of the tobacco on the nasal or oral mucosa, but which arenot subject to the disadvantages of a strong minty flavour and storageinstability.

It is a yet further object of the present invention to provide animproved method of imparting to tobacco and tobacco-containingmanufactures a physiological cooling activity.

According to the present invention, therefore, there are also providedtobacco and tobacco-containing manufactures comprising tobacco and acold receptor stimulating additive, present in an amount effective tostimulate the cold receptors of the nervous system of mucous membranesof the oral and nasal mucosa when the tobacco or tobacco-containingmanufacture is smoked, chewed or inhaled by the human user, saidadditive being a cold receptor stimulating compound of formula (I)hereinbefore defined.

By tobacco and tobacco-containing manufactures we mean any article, suchas cigarette or cigar, or any composition, such as pipe or chewingtobacco or snuff, containing tobacco in a prepared form ready forutilisation by the human person whether by smoking, i.e. burning of theprepared tobacco and inhalation of the tobacco smoke, chewing or directinhalation of the tobacco.

In formulating the tobacco and tobacco-containing manufactures of thisinvention the active compound may be incorporated directly into thetobacco, for example, by impregnation of the tobacco with an alcoholicsolution of the active ingredient, at a suitable stage of manufacture.However, in an alternative and preferred arrangement the activeingredient may be incorporated into a tobacco smoke filter for use in apipe or cigarette filter or as a filter tip for cigarettes. The latter,in particular, forms a particularly effective utilisation of the presentinvention, the active compound simply being impregnated in the wad ofmaterial forming the filter tip. This may be of any of the well knowntypes of filter tip for cigarettes, e.g. a filter pad of celluloseacetate, paper, cotton, α-cellulose or asbestos fiber. Conveniently thefilter tip is impregnated with an alcoholic solution of the activecompound and then dried to deposit the active compound therein.

The amount of active compound to be incorporated into the tobacco ortobacco-containing manufacture in accordance with the invention willvary from compound to compound depending on the activity thereof, i.e.the amount thereof which it is necessary to place in contact with theskin to produce a noticeable cooling effect, and will depend also on themode of application thereof, i.e. whether the compound is impregnated inthe tobacco itself, or in a filter tip or in any other accessory.However, the actual amount is not critical to this invention and will bereadily determinable by the person skilled in the art by means of a fewsimple tests. As a matter of guidance, however, it may be mentioned thatwith the more active compounds, as little as 0.1 mg. deposited on thefilter tip of a tipped cigarette is effective.

This latter aspect of the invention is illustrated by the followingExamples.

EXAMPLE 37 Cigarette Tobacco

A proprietary brand of cigarette tobacco was sprayed with an ethanolicsolution of N,N-di-isobutyl-N',N'-dimethyl urea and was rolled intocigarettes each containing approximately 0.5 mg. of active compound.Smoking the impregnated cigarettes produced a cool effect in the mouthcharacteristic of mentholated cigarettes but without any attendant odourother than that normally associated with tobacco.

Impregnation of the filter tip of a proprietary brand of tippedcigarette with 0.5 mg. of N,N-di-sec-butyl acetamide produced a similareffect.

EXAMPLE 38 Cigarette Tobacco

A proprietary brand of cigarette tobacco was sprayed with an ethanolicsolution of N-(2,4,4-trimethylpent-2-yl) propionamide and was rolledinto cigarettes each containing approximately 0.5 mg. of activecompound. Smoking the impregnated cigarettes produced a cool effect inthe mouth characteristic of mentholated cigarettes.

EXAMPLE 39 Filter Tip Cigarette

The filter tip of a proprietary brand of cigarette was impregnated withan ethanol solution of N,N-disec.butyl methanesulphonamide in an amountsufficient to deposit in the filter 0.5 mg. of the active compound.Smoking the cigarette with the impregnated tip gave rise to a noticeablecooling effect in the mouth.

EXAMPLE 40 Pipe Tobacco

A proprietary brand of pipe tobacco was sprayed with an ethanolicsolution of N-n-butyl-N-t-butyl-N'-ethylurea. 2g. of the tobaccocontaining 0.5 mg. of the active compound was placed in a pipe. Smokingthe impregnated tobacco produced a cool effect in the mouthcharacteristic of mentholated tobacco but without any attendant odourother than that normally associated with tobacco.

EXAMPLE 41 Cigars

The tobacco of a proprietary brand of cigar was impregnated with anethanolic solution of N-(1,3-dimethylbutyl)-N-ethylpropionamide in anamount sufficient to deposit in the cigar 0.5 mg. of the activecompound. Smoking the cigar with the impregnated tobacco gave rise to anoticeable cooling effect in the mouth.

EXAMPLE 42 Chewing Tobacco

A proprietary brand of chewing tobacco was impregnated with an ethanolicsolution of N-acetyl-2,6-dimethylpiperidine. 1g. of the tobaccocontaining 0.2 mg. of active compound was used. Chewing the impregnatedtobacco produced a cool effect in the mouth.

EXAMPLE 43 Snuff

A proprietary brand of snuff was impregnated with an ethanolic solutionof N-isobutyl-N-sec.butyl-N'-isopropylurea. 1g. of the snuff wasimpregnated with 5 mg. of active compound. About 0.01 g. of theimpregnated snuff produced a cool effect in the nose when inhaled.

EXAMPLE 44 Cigarette Tobacco

A proprietary brand of cigarette tobacco was sprayed with an ethanolicsolution of N,N-disec.butyl ethanesulphonamide and was rolled intocigarettes each containing approximately 0.5 mg. of active compound.Smoking the impregnated cigarettes produced a cool effect in the mouthcharacteristic of mentholated cigarettes but without any attendant odourother than that normally associated with tobacco.

EXAMPLE 45 Filter Tip Cigarette

The filter tip of a proprietary brand of cigarette was impregnated withan ethanolic solution ofN-[N'-ethyl-N'-(1,2-dimethyl-n-propyl)carbamoyl]pyrrolidine in an amountsufficient to deposit in the filter 0.5 mg. of the active compound.Smoking the cigarette with the impregnated tip gave rise to a noticeablecooling effect in the mouth.

We claim:
 1. In a manufactured consumer product for application to orconsumption by the human body and being:(a) a personal care productcomprising a topically or orally administrable base medium containing aflavourant, clourant, perfume, surface active agent or antiseptic agent;(b) an ingestible preparation comprising an edible or potable basecontaining a flavourant or colourant; (c) a pharmaceutical preparationcomprising a topically or orally administrable pharmaceuticallyacceptable carrier and an active pharmaceutical ingredient; or (d) atobacco containing consumer product, said consumer product alsocontaining an ingredient capable of stimulating the cold receptors ofthe nervous system of the surface tissues of the body when brought intocontact therewith by application or consumption of the said product, theimprovement which comprises using as said cold receptor stimulatingingredient an effective amount of an amide of the formula: ##STR9##wherein R₁ is H, C₁ -C₇ alkyl or C₃ -C₆ cycloalkyl; R₂ is C₃ -C₈ alkylor C₃ -C₈ alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkyl orcycloalkylalkyl, with the proviso that R₂ is branched at an alpha carbonatom relative to the N atom when R₁ is H, or at an alpha or beta carbonatom when R₁ is alkyl or cycloalkyl, this condition being satisfied inthe case of cyclic groups when the carbon atom attached to the N atom ispart of the cycle; R₁ and R₂ together provide a total of at least 5carbon atoms; R₃ is H, C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₂ -C₈hydroxyalkyl, C₂ -C₈ carboxyalkyl or C₃ -C₈ alkylcarboxyalkyl, with theproviso that when R₃ is C₆ alkyl it is primary in structure; and R₁, r₂and the group --COR₃ together provide a total of from 7-16 carbon atoms.2. A product according to claim 1, wherein R₁ is H or C₁ -C₇ alkyl, R₂is C₃ -C₈ alkyl or C₃ -C₈ cycloalkyl, cycloalkylalkyl, oralkylcycloalkyl, R₂ having branching at an alpha carbon atom when R₁ isH or at an alpha or beta carbon atom when R₁ is alkyl, and R₃ is H, C₁-C₆ alkyl, or C₂ -C₆ hydroxyalkyl, carboxyalkyl or alkylcarboxyalkyl orC₃ -C₆ cycloalkyl.
 3. A product according to claim 1, which is a toiletor cosmetic lotion comprising an aqueous, alcoholic or aqueous alcoholiccarrier, an antiseptic or odourant, and an effective amount of said coldreceptor stimulating compound.
 4. A product according to claim 1, whichis a toilet or cosmetic lotion or cream comprising an oleaginouscarrier, an antispetic or odourant, and an effective amount of said coldreceptor stimulating compound.
 5. A product according to claim 1, whichis a shaving foam preparation comprising a foamable base, a surfactant,an odourant, or antiseptic, and an effective amount of said coldreceptor stimulating compund.
 6. A product according to claim 1, whichis a dentifrice comprising an effective amount of said cold receptorstimulating compound.
 7. A product according to claim 1, which is amouthwash comprising an aqueous or aqueous-alcoholic carrier, anantiseptic, and an effective amount of said cold receptor stimulatingcompound.
 8. A product according to claim 1, which is a chewing gum,comprising an edible chewing gum base, a flavourant and an effectiveamount of a cold receptor stimulating acyclic carboxamide of the formuladefined in claim
 23. 9. A method of stimulating the cold receptors ofthe nervous system in the surface tissues of the human body whichcomprises contacting said receptors with an effective amount of a coldreceptor stimulating compound of the formula defined in claim
 1. 10. Aproduct according to claim 1, which is a cigarette containing aneffective amount of said cold receptor stimulating compound.
 11. Aproduct according to claim 1, which is a filter tip cigarette containingan effective amount of said cold receptor stimulating compoundimpregnated in the filter tip.